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TRIM65-catalized Ubiquitination is Essential for MDA5-mediated Antiviral Innate Immunity

Overview
Journal J Exp Med
Date 2016 Dec 30
PMID 28031478
Citations 91
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Abstract

MDA5 plays a critical role in antiviral innate immunity by functioning as a cytoplasmic double-stranded RNA sensor that can activate type I interferon signaling pathways, but the mechanism for the activation of MDA5 is poorly understood. Here, we show that TRIM65 specifically interacts with MDA5 and promotes K63-linked ubiquitination of MDA5 at lysine 743, which is critical for MDA5 oligomerization and activation. Trim65 deficiency abolishes MDA5 agonist or encephalomyocarditis virus (EMCV)-induced interferon regulatory factor 3 (IRF3) activation and type I interferon production but has no effect on retinoic acid-inducible I (RIG-I), Toll-like receptor 3 (TLR3), or cyclic GMP-AMP synthase signaling pathways. Importantly, Trim65 mice are more susceptible to EMCV infection than controls and cannot produce type I interferon in vivo. Collectively, our results identify TRIM65 as an essential component for the MDA5 signaling pathway and provide physiological evidence showing that ubiquitination is important for MDA5 oligomerization and activation.

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References
1.
Takeuchi O, Akira S . MDA5/RIG-I and virus recognition. Curr Opin Immunol. 2008; 20(1):17-22. DOI: 10.1016/j.coi.2008.01.002. View

2.
Jiang X, Chen Z . The role of ubiquitylation in immune defence and pathogen evasion. Nat Rev Immunol. 2011; 12(1):35-48. PMC: 3864900. DOI: 10.1038/nri3111. View

3.
Didierlaurent A, Brissoni B, Velin D, Aebi N, Tardivel A, Kaslin E . Tollip regulates proinflammatory responses to interleukin-1 and lipopolysaccharide. Mol Cell Biol. 2006; 26(3):735-42. PMC: 1347014. DOI: 10.1128/MCB.26.3.735-742.2006. View

4.
Gack M, Shin Y, Joo C, Urano T, Liang C, Sun L . TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity. Nature. 2007; 446(7138):916-920. DOI: 10.1038/nature05732. View

5.
Versteeg G, Rajsbaum R, Sanchez-Aparicio M, Maestre A, Valdiviezo J, Shi M . The E3-ligase TRIM family of proteins regulates signaling pathways triggered by innate immune pattern-recognition receptors. Immunity. 2013; 38(2):384-98. PMC: 3584420. DOI: 10.1016/j.immuni.2012.11.013. View